This invention relates to liquid aqueous suspension or dispersion formulations, particularly to stable oral pharmaceutical formulations comprising amoxycillin trihydrate and potassium clavulanate. These may be referred to as co-amoxiclav formulations. The invention also relates to the powder formulations for reconstitution as aqueous suspensions, and the granulate formulations for preparation of aqueous dispersions.
Amoxycillin is a well known broad-spectrum semisynthetic betalactam antibiotic effective against many gram-positive and gram-negative microorganisms. In combination with the xcex2-lactamase inhibitor clavulanic acid, amoxycillin is also active against bacterial strains which are normally resistant to betalactam antibiotics. Gastrointestinal intolerance is often reported in patients treated with antibiotics, especially in children and sensitive individuals. Thus, there is the need for developing effective stable pharmaceutical formulations containing amoxycillin and clavulanic acid which have an acceptable taste and reduced gastrointestinal intolerance.
Sugars (such as glucose, fructose, lactose and maltose) and polyols (such as mannitol, sorbitol and xylitol) are often used as excipients in pharmaceutical formulations for preparation of powders for reconstitution as suspensions or granulates for preparation dispersions in water. Sugars and polyols endow the pharmaceutical product with a pleasant taste which is very important in pediatric use. When used in greater quantities as fillers in oral formulations, they have a laxative effect.
In order to minimise gastrointestinal intolerance of the amoxycillin/clavulanic acid suspensions, sugar or mannitol have been replaced with silicon dioxide. However these suspensions have a less pleasant taste.
Attempts have been made to reduce gastrointestinal side effects caused by the drugs containing amoxycillin plus clavulanic acid by using various additives. WO97/07408 discloses amoxycillin/clavulanic acid formualations to which pharmaceutically acceptable organic acid or salts thereof are added to reduce gastrointestinal intolerance. WO97/06798 discloses clavulanate formulations containing pharmaceutically acceptable salts of alkaline earth metals and inorganic acids to minimise gastrointestinal intolerance.
Addition of various metal salts, especially when greater amounts of silicon dioxide are present, potentiates an unpleasant taste making use of such formulations unacceptable.
According to a first aspect of the present invention there is provided a dry powder formulation adapted for reconstitution with water and containing as active ingredients amoxycillin trihydrate and potassium clavulanate, and cellulose as the filler, the formulation optionally further including one or more pharmaceutically acceptable excipients selected from: flavourings, sweeteners, buffering agents, stabilisers, and viscosity modifiers.
In an embodiment the present invention also provides a reconstituted aqueous suspension derived from the dry formulation and containing a unit dosage of active ingredients in 5 ml.
Formulations in accordance with this invention provide an amoxycillin trihydrate/potassium clavulanate powder for reconstitution as a suspension and amoxycillin trihydrate/potassium clavulanate granulates for preparing dispersions in water for oral administration which have reduced gastrointestinal intolerance and acceptable pleasant taste. The taste of the suspension is especially important in pediatric use. The aim of the invention is achieved by use of cellulose, either microcrystalline or powdered, as a sole filler. Generally other types of celluloses which have greater swelling ability, are used for preparation of suspensions in lower concentrations (0.2 to 5%) acting as viscosity-increasing agent (thickener). Microcrystalline cellulose is used primarily as a diluent in oral tablet and capsule formulations.
Microcrystalline cellulose with a particle size from 20 to 100 xcexcm is preferred. Suitable grades include Avicel types pH 101, 102, 103, 104, 112, 113, 301 and 302. These differ in physical characteristics such as particle size, bulk density, loss on drying, viscosity and chemical characteristics such as the degree of polymerization.
The percentages or amounts referred to in this specification are by weight unless indicated otherwise. Percentages or proportions are selected to total 100%.
In the formulations of this invention, predried cellulose (to reduce free water content which has an unfavourable impact on clavulanic acid stability) used as a filler acting simultaneously as a viscosity-increasing agent and a stabilising agent provides the good stability of the reconstituted suspension over the 7- to 10-day period of use. The amount of cellulose, as a principal filler in the formulation, may range from 5 to 70% w/w, preferably 20 to 70% w/w, more preferably 20 to 60% w/w of the dry formulation. The percentage of the active substances is from 20 to 70%.
Microcrystalline cellulose (Avicel, Emcocel, Vitacel) with an average particle size of 20 xcexcm or preferably microcrystalline cellulose of average particle size of 50 xcexcm may be used. Powdered cellulose (Vivacel, Elcema, SolkaFlok) having different particle size or as granulated powder may be used. In preferred embodiments the microcrystalline cellulose acts as a desiccant to protect the moisture sensitive clavulanate, leading to improved long term stability of the formulation.
Cellulose in the combination with sugars or polyols in the quantities devoid of a laxative effect may be used.
The formulations of this invention may also contain auxiliary ingredients which may be essentially conventional in the art. To improve the taste, flavours and sweetening agents, preferably saccharin, saccharin sodium or aspartame in the amounts allowable for oral formulations may be added. Flavours which may be used may comprise common flavours like strawberry, cherry, wild cherry, lemon, banana, raspberry, orange, caramel or mixtures thereof, which in combination with the antibiotic provide a pleasant flavour and taste.
Suitable excipients may include buffering agents such as different acids and their salts, eg citric acid, sodium citrate, succinic acid, swelling agents and viscosity-increasing agents such as suspension stabilisers and other additives.
The formulations of present invention are suitable for BID or TID administration in the prescribed dose. They are indicated in the treatment of children, adults and the elderly, and patients with difficulty in swallowing.
The present formulations relate to the combination of clavulanic acid and amoxycillin in a weight ratio of 1:1 to 1:20, preferably from 1:4 and 1:8. The formulations relate to the powder for suspension or granulation for dispersion in water for oral administration in the following doses:
Other dosages may also be used.
The powder or the granulation should be stored in air-tight screwcap bottles or plastic containers or in sachets for preparation of suspension or dispersion, respectively, immediately prior to use.
The formulations of the present invention can be produced using the conventional manufacturing procedures such as homogenisation, sieving and milling. A portion of the ingredients may be pre-granulated, or granulated ingredients are used to improve powder flowability, which is especially important for sachet packaging.
Predried or anhydrous ingredients should be used in the formulation. Cellulose or a combination of cellulose and sodium carboxymethylcellulose should be dried in tray or vacuum dryers to LOD less than 1%. Additional drying of the ingredients yields the powder and or granulate respectively, with a low moisture content, eg below 6%.
Clavulanic acid and salts thereof are extremely sensitive to the presence of moisture and free water and undergo rapid hydrolytic degradation. Therefor, the formulations of this invention should be manufactured in suitable air-conditioned production areas with relative humidity (RH) less than 30% and temperature below 25xc2x0 C.
The invention is further described by means of example, but not in any imitative sense.